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Armstrong, Andrew J; Halabi, Susan; Luo, Jun; Nanus, David M; Giannakakou, Paraskevi; Szmulewitz, Russell Z; Danila, Daniel C; Healy, Patrick; Anand, Monika; Rothwell, Colin J; Rasmussen, Julia; Thornburg, Blair; Berry, William R; Wilder, Rhonda S; Lu, Changxue; Chen, Yan; Silberstein, John L; Kemeny, Gabor; Galletti, Giuseppe; Somarelli, Jason A; Gupta, Santosh; Gregory, Simon G; Scher, Howard I; Dittamore, Ryan; Tagawa, Scott T; Antonarakis, Emmanuel S; George, Daniel J
Journal of clinical oncology, 05/2019, Volume: 37, Issue: 13Journal Article
Androgen receptor splice variant 7 (AR-V7) results in a truncated receptor, which leads to ligand-independent constitutive activation that is not inhibited by anti-androgen therapies, including abiraterone or enzalutamide. Given that previous reports suggested that circulating tumor cell (CTC) AR-V7 detection is a poor prognostic indicator for the clinical efficacy of secondary hormone therapies, we conducted a prospective multicenter validation study. PROPHECY ( ClinicalTrials.gov identifier: NCT02269982) is a multicenter, prospective-blinded study of men with high-risk mCRPC starting abiraterone acetate or enzalutamide treatment. The primary objective was to validate the prognostic significance of baseline CTC AR-V7 on the basis of radiographic or clinical progression free-survival (PFS) by using the Johns Hopkins University modified-AdnaTest CTC AR-V7 mRNA assay and the Epic Sciences CTC nuclear-specific AR-V7 protein assay. Overall survival (OS) and prostate-specific antigen responses were secondary end points. We enrolled 118 men with mCRPC who were starting abiraterone or enzalutamide treatment. AR-V7 detection by both the Johns Hopkins and Epic AR-V7 assays was independently associated with shorter PFS (hazard ratio, 1.9 95% CI, 1.1 to 3.3; = .032 and 2.4 95% CI, 1.1 to 5.1; = .020, respectively) and OS (hazard ratio, 4.2 95% CI, 2.1 to 8.5 and 3.5 95% CI, 1.6 to 8.1, respectively) after adjusting for CTC number and clinical prognostic factors. Men with AR-V7-positive mCRPC had fewer confirmed prostate-specific antigen responses (0% to 11%) or soft tissue responses (0% to 6%). The observed percentage agreement between the two AR-V7 assays was 82%. Detection of AR-V7 in CTCs by two blood-based assays is independently associated with shorter PFS and OS with abiraterone or enzalutamide, and such men with mCRPC should be offered alternative treatments.
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